Statins are widely used as cholesterol lowering therapeutic agents. They reduce cholesterol levels through competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the key enzyme that regulates cholesterol synthesis. The cholesterol-lowering effect of statins is also due to an increase in the uptake of cholesterol by cells as a result of intracellular cholesterol depletion and enhanced expression of low-density lipoprotein (LDL) receptors.
However, statins exhibit properties that are beyond their lipid-lowering effects. These non-lipid-lowering properties involve the inhibition of the isoprenoid pathway including the cholesterol precursor mevalonate which is required as a precursor for the prenylation of a number of proteins leading to a change in function [Drugs of Today; 2004; 40: 975-990]. For example simvastatin modulates chemokine and chemokine receptor expression by geranylgeranyl isoprenoid pathway in human endothelial cells and macrophages [Veillard N R et al; Simvastatin modulates chemokine and chemokine receptor expression by geranylgeranyl isoprenoid pathway in human endothelial cells and macrophages; Atherosclerosis; 2005 Nov. 28; Epub ahead of print]. Statins also have a potential role as antioxidants leading to downregulation of inflammation [Drugs of Today; 2004; 40: 975-990]. Recent research data demonstrated that statins inhibit the induction of the major histocompatibility (MHC) class II expression by interferon-gamma (IFN-gamma), leading to repression of MHC II-mediated T-cell activation. Furthermore, statins inhibit the expression of specific cell surface receptors on monocytes, adhesion molecules and also integrin-dependent leucocyte adhesion [Timely Top Med Cardiovasc Dis; 2005; 9: E3]. Statins exhibit additional effects on inflammation by decreasing IL-6, IL-8, and MCP-1 synthesis in human vascular smooth muscle cells (VSMC) in vitro [Cardiovas Res; 2003; 59: 755-66]. Simvastatin inhibits growth factor expression and modulates profibrogenic markers in lung fibroblasts [Am J Respir Cell Mol Biol. 2005; 32: 290-300]. Furthermore, statins increase bioavailability of nitric oxide. Cerivastatin increased eNOS expression a NO release in human endothelial cells [J Physiol Pharmacol. 2002; 53:585-95]. In vivo statins exert anti-inflammatory effects in many models of inflammatory airway diseases like asthma and COPD. Simvastatin was shown to inhibit pulmonary inflammatory cell accumulation and IL-4 and IL-5 release into the alveolar lumen after allergen challenge in mice [J Immunol. 2004; 172: 2903-8]. Simvastatin inhibits cigarette smoking-induced emphysema and pulmonary hypertension in rat lungs [Am J Respir Crit Care Med. 2005; 172: 987-93]. Overall statins exhibit inhibitory properties on inflammation and modulation on the immune system.
In the international patent application WO00/48626 (University of Washington) aerosol compositions of HMG-CoA reductase inhibitors for inhibiting inflammation associated with a pulmonary disease, such as asthma, interstitial pneumonitis, emphysema, chronic bronchitis, adult respiratory distress syndrome (ARDS) and cystic fibrosis, are described. In EP1275388 (Takeda) several statins are described as useful for the treatment of TNFα associated diseases such as inflammatory diseases including asthma and COPD. In US20050119330 the use of HMG-CoA reductase inhibitors is described for the treatment of lung proliferative vascular disorders, such as for example, pulmonary hypertension and pulmonary fibrosis.
There is pressing need to improve the treatment of inflammatory pulmonary diseases like asthma and COPD. These inflammatory diseases are characterized by multifactorial pathologies. Several inflammatory mediators are involved as well as various cell types. Therefore, in medical practice for the treatment of e.g. asthma and COPD the targeting of a single mediator or cell type has not lead to satisfactory results. For both asthma and COPD at present combination therapies are used but in many instances with limited success especially in COPD.
Cyclic nucleotide phosphodiesterase (PDE) inhibitors, particularly inhibitors of type 4 (PDE4), are useful in the treatment of a variety of allergic and inflammatory diseases, for example in respiratory diseases, such as asthma and chronic obstructive pulmonary disease.
HMG-CoA reductase inhibitors, by a route different from PDE4 inhibitors, are also useful in the treatment of inflammatory diseases.
It would be desirable to provide combinations and methods of treatment that can take advantage of the different therapeutic pathways of a PDE4 inhibitor and a HMG-CoA reductase inhibitor to more effectively treat inflammatory disorders, in particular asthma and COPD.